Expression of VEGF‐C and VEGF‐D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma

Onogawa, Seiji; Kitadai, Yasuhiko; Tanaka, Shinji; Kuwai, Toshio; Kimura, Shigeru; Chayama, Kazuaki

doi:10.1111/j.1349-7006.2004.tb03167.x

Cited by 134 publications

(112 citation statements)

References 48 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Using animal models, VEGF-C induced formation of new lymph vessels in the chick chorioallantoic membrane (Oh et al, 1997), induced lymphangiogenesis around islet of Langerhans in the pancreas which, normally, are not surrounded with lymphatics (Mandriota et al, 2001), induced hyperplasia and dilatation of the dermal lymphatics when overexpressed in transgenic mice and increased LVD and LN metastasis in xenografted breast cancer (Skobe et al, 2001). The present study reports a significant association between expression of VEGF-C and LVD similar to other findings reported in breast cancer (Nakamura et al, 2005) and other tumour types (Yonemura et al, 1999;Onogawa et al, 2004). This is mostly likely due to the stimulatory effect of VEGF-C on VEGFR-3 and a9 b1 integrin on the LEC surface.…”

Section: Discussionsupporting

confidence: 91%

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

et al. 2007

View full text Add to dashboard Cite

Vascular endothelial cell growth factors (VEGF)-A, -C and -D have potent angio and lymphangiogenic functions in experimental models, although their role in the progression of human breast cancer is unclear. The aims of the current study were to examine the relationship between the expression of the aforementioned growth factors with the angio and lymphangiogenic characteristics of breast cancer, and to assess their suitability as potential prognostic factors. Paraffin-embedded sections of 177 primary invasive breast cancer, with complete clinical follow-up information for 10 years, were stained for VEGF-A, -C, -D, podoplanin and CD34 using standard immunohistochemical approaches. The expression of the growth factors was correlated with clinicopathological criteria and patients' survival. Lymph vessel density (LVD) and microvessel density (MVD) were assessed and correlated with expression of the growth factors. Vascular endothelial cell growth factor-A, -C and -D were highly expressed in 40, 37 and 42% of specimens, respectively. High expression of VEGF-A and -C, but not of -D, was associated with a higher LVD (P ¼ 0.013 and P ¼ 0.014, respectively), a higher MVD (Po0.001 and P ¼ 0.002, respectively), the presence of lymph node metastasis (Po0.001 and Po0.001, respectively), distant metastasis (P ¼ 0.010 and P ¼ 0.008, respectively) and a shorter Overall Survival (P ¼ 0.029 and 0.028, respectively). In conclusion, breast cancers that express high levels of VEGF-A and -C are characterised by a poor prognosis, likely through the induction of angio and lymphangiogenesis. Examination of expression of VEGF-A and -C in breast cancer may be beneficial in the identification of a subset of tumours that have a higher probability of recurrence and metastatic spread.

show abstract

Section: Discussionsupporting

confidence: 91%

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Forced VEGF-C overexpression in a VEGF-C-nonexpessing and nonmetastatic human breast cancer cell line MCF-7 resulted in enhanced tumour growth in vivo, lymphangiogenesis and lymphatic metastasis in immunodeficient mice (Mattila et al, 2002). Elevated expression of VEGF-C in tumour tissues has been shown to have a negative influence on prognosis and a positive correlation with lymph node metastasis in many cancers including cancers of the breast (Nakamura et al, 2003), uterine cervix (Fujimoto et al, 2004), colon and rectum (Onogawa et al, 2004), oesophagus (Kimura et al, 2003), stomach (Duff et al, 2003a), head and neck (O-charoenrat et al, 2001), and gallbladder (Nakashima et al, 2003). Additionally, serum VEGF-C was shown to be elevated in patients with non-small cell lung cancer (Tamura and Ohta, 2003) and colorectal cancer (Duff et al, 2003b), and in the former case, this was also correlated with lymph node metastasis.…”

mentioning

confidence: 99%

COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

et al. 2006

View full text Add to dashboard Cite

Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE 2 . Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors.

show abstract

“…Elevated VEGF-C expression was reported in patients with prostatic carcinoma and oesophageal squamous cell carcinoma (Tsurusaki et al, 1999;Kitadai et al, 2001) but is controversial with regard to AML patients (Fielder et al, 1997;Dias et al, 2002;Loges et al, 2005). In contrast, decreased VEGF-D expression levels were reported in patients with lung adenocarcinoma and colorectal carcinoma (Niki et al, 2000;Onogawa et al, 2004). However, no previous reports addressed plasma VEGF-C and -D levels. Both Ang-1 and -2 can only bind to the Tie-2 receptor, but they have opposite effects on Tie-2 activation.…”

mentioning

confidence: 99%

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

Tien

et al. 2007

Br J Cancer

View full text Add to dashboard Cite

Bone marrow (BM) neoangiogenesis plays an important role in acute myelogenous leukaemia (AML), and depends on the interplay of members of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang) families. We determined the marrow levels of seven molecules associated with angiogenesis in 52 AML patients before chemotherapy and 20 healthy controls: VEGF-A, VEGF/PlGF, VEGF-C, VEGF-D, Ang-1, Ang-2, and Tie-2. All the molecules were quantified using enzyme-linked immunosorbent assay (ELISA). Comparing to normal controls, the marrow levels of VEGF/PlGF, Ang-2, and Tie-2 were significantly higher, and those of VEGF-C and Ang-1 were significantly lower in the AML patients ( P <0.001). A total of 31 patients were further subjected to survival analysis. Patients with lower Tie-2 (<26 ng ml −1 ) and Ang-2 levels (<4500 pg ml −1 ) displayed a survival advantage ( P =0.037 and 0.042, respectively), same as patients with higher VEGF/PlGF (⩾1 pg ml −1 ) and VEGF-D levels (⩾350 pg ml −1 ) ( P =0.020 and 0.016, respectively). An angio-index ((Ang-2 × Tie-2)/(VEGF/PlGF × VEGF-D)) was established and multivariate Cox regression analysis revealed that patients with higher angio-index values (⩾50) displayed poor prognosis (hazard ratio 5.91, 95% confidence interval 1.99–17.56; P =0.001). The angio-index is closely associated with the clinical outcome of AML patients and may be valuable in disease prognosis.

show abstract

Expression of VEGF‐C and VEGF‐D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma

Abstract: olorectal carcinoma is one of the world's most common malignancies, and the prognosis of patients with colorectal carcinoma is dependent on the presence of lymph node metastasis.

Cited by 134 publications

References 48 publications

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

Contact Info

Product

Resources

About